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Traditional Chinese Medicine
CHAPTER
Traditional Chinese Medicine: Current State, Challenges, and Applications
1
Xijun Wang, Aihua Zhang, Hui Sun, Guangli Yan, Ping Wang, Ying Han
1. CURRENT STATE The 2015 Nobel Prize for Physiology or Medicine, won by pharmacologist Youyou Tu, was the first science Nobel Prize awarded to a China-based scientist. Tu’s discovery of artemisinin—a key antimalarial drug credited with saving millions of lives—was rooted in ancient Chinese herbal medicine (Tu, 2011). It has brought traditional Chinese medicine (TCM) to the forefront of the global research community’s attention. Globally, scientists are frequently looking for therapeutic agents from TCM, which is a rich source of potential leads for drug development. Shifting the current drug discovery tide from “finding new drugs” to “screening natural products” may be helpful for overcoming the “more investment, fewer drugs” challenge. The World Health Organization estimates that 80% of the world’s population relies on herbs for their primary health care needs (Zhang et al., 2013). TCM, which is an essential part of the health care system in most Asian countries, relies on natural products and has been playing a very important role in health protection and disease control for thousands of years. TCM therapeutic efficacy, usually attributed to the synergistic property of multiple herbs and constituents, has advocated combinatorial therapeutic strategies called formulae that improve efficacy through hitting multiple targets. Based on syndromes and patient characteristics, and guided by the TCM theory, formulae are designed to contain a combination of various kinds of crude drugs that, when combined, generally assume that a synergism of all ingredients will bring about the maximum of therapeutic efficacy (Fig. 1.1A). Typically, according to the principle of TCM, the herbal formulae include four elements: the monarch (Jun), minister (Chen), assistant (Zuo), and servant (Shi). In TCM formulae, monarch aims at the cardinal pathological symptom of a disease. Minister assists monarch to treat other secondary symptoms, if applicable. Assistant and servant mainly coordinate the formulae, facilitate performances of monarch and minister, and decrease their side effects. They work together harmoniously to achieve an ideal therapeutic outcome. However, the direct effect substances in vivo Serum Pharmacochemistry of Traditional Chinese Medicine. http://dx.doi.org/10.1016/B978-0-12-811147-5.00001-7 Copyright © 2017 Elsevier Inc. All rights reserved.
1
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CHAPTER 1 Traditional Chinese Medicine
FIGURE 1.1 The Characteristics of Traditional Chinese Medicine (TCM) on Ancient Chinese Philosophy. (A) TCM practitioners often prescribe a combination of herbs called formulae that work together harmoniously to achieve an ideal therapeutic outcome. (B) Formulae consisting of multiherbs possess multicomponent and multitarget characteristics.
2. Application of TCM
are poorly understood and thus hamper the modernization of TCM; they must be addressed using modern analytical techniques coupled with innovative methodology. Some researchers have made good attempts in this area using approaches to identify the multicomponents from herb medicines (Song et al., 2016; Wang et al., 2016). These studies can be considered a useful pilot trial in the effort to evaluate traditional formulae on a larger scale. Furthermore, these observations indicate that traditional formulae usually require multiple components to exert their effects, possibly laying the foundation for promising new schemes and patterns of advancing drug development from active constituents of formulae toward better therapeutic effects. TCM, one of the oldest phytomedicine systems of health care, has been used in Asian countries such as China, Japan, and Korea for thousands of years. Based on its long history of clinical use and wide-ranging effects in the treatment of numerous diseases, especially chronic diseases, TCM is increasingly accepted and used by billions of people around the world. For improving health, practitioners advocated combinatorial therapeutic strategies based on overall symptoms and signs of syndrome and often prescribe formulae that work together harmoniously to achieve ideally therapeutic effects. A single herb already contains thousands of compounds; formulae consisting of multiherbs possess multicomponent and multitarget characteristics (Fig. 1.1B). Compared with chemical drugs, TCM has multicomponent, multitarget, and multipathway characteristics and possesses unparalleled advantages when faced with miscellaneous diseases. This means that the efficacy of TCM depends on the combined action of multiple herbs because it usually contains a lot of ingredients and exerts synergistic therapeutic efficacies. However, this can cause many difficulties in the search for effective substances from TCM.
2. APPLICATION OF TCM TCM is based on ancient Chinese philosophy. Its characteristics include yin yang theories, five element concepts, subjective diagnostic methods, holism, treatment of differential syndromes, dynamic functional aspects, etc. TCM treatment with therapeutic strategies in a holistic fashion is based on overall symptoms and signs of differential syndromes and, from a nonlinear point of view, concerns disease from various dynamic functional aspects. It focuses on the patient rather than the disease, promoting enhanced quality of life. TCM often uses formulae that comprise several types of crude herbs tailored to an individual’s condition based on subjective diagnosis methods. TCM advocates combinatory therapeutic strategies by formulae, in which one represents the key component and others serve as adjuvants to assist the effects or facilitate the delivery of the key components (Wang et al., 2013). According to TCM theory, formulae include four elements: the monarch (which plays the most important role in the formulae), the minister (which increases the effectiveness of the monarch herb), the assistant (which helps the monarch and minister herbs reach their target positions), and the servant (which can reduce the adverse effects and/or increase the potency of the whole formulae).
3
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CHAPTER 1 Traditional Chinese Medicine
Because of a long cultural heritage and rich natural resources, a wealth of knowledge of traditional medicine has been accumulated in China. At least 11,146 plant species, 1581 animal species, and 80 minerals and substances, ranging from precious stones to mineralized fossils, are used as TCM medicines (Liu et al., 2013). Typically, formulae, which consist of several herbs, would comprise hundreds of compounds as a complex system that contains lots of components with diversities in chemical structures, biological activities, and interactions among compounds, and the content for each component varies greatly. Many Chinese therapeutic herbs traditionally used in the cotreatment but not monotreatment series demonstrate significantly better pharmacological effects, because the combination application of TCM can achieve a synergistic interaction capable of yielding a sufficient effect at low doses. Tremendous progress has been made in the past few years; however, cancer, diabetes, and other complex diseases may limit the performance of the single-target-drug paradigm. Meanwhile, some researchers found that a combination of multiple compounds rather than using a single compound could achieve increased effectiveness (Zhang et al., 2014). With the wave of “returning to nature,” people from all over the world are becoming increasingly interested in the magical effects of the formulae. Like almost all other traditional medicines, at present formulae are still being practiced in their original form and although effective in treating many conditions, they lack necessary scientific research. The lack of a comprehensive understanding of the relationship between syndrome and formulae makes it difficult to advance TCM from modern sciences, which stagnates the development of TCM. For TCM to be modernized, it is critical to use modern tools to determine its mechanism of action.
3. THE COMING ERA OF PRECISION MEDICINE: WHAT CAN WE LEARN FROM CHINESE MEDICINE? President Obama in the State of the Union Address announced the launch of a new Precision Medicine Initiative (Fox, 2015). Precision medicine promises to match the right patient with the right diagnosis, the right treatment, in the right amount. The era of personalized precision medicine is about to emerge. The “personalized treatment” of TCM is consistent with the ideology of precision medicine. Obviously, compared with modern medicine, TCM leans toward “precision,” reflecting “personalized medicine,” because it has a complete theoretical system and a mature method for the diagnosis of an individual’s condition. After the development and improvement of TCM by ancient physicians, TCM formed the coordination of theory and practice of precise diagnosis and precise treatment in a dynamic state. Chinese medicine adjusts the physique of patients by way of syndrome differentiation, something that Western medicine cannot do. TCM treatment in a holistic fashion is based on overall symptoms and signs of syndromes, and concerns disease from various dynamic functional aspects (Liu et al., 2016). It focuses on the patient rather than the disease, promoting and enhancing the quality of life. TCM often uses formulae that are comprised of several crude herbs tailored to an individual’s condition based on
5. Future Perspective
subjective diagnosis. Interestingly, to improve clinical efficacy, formulae variation with syndrome and formulae corresponding syndrome have practical significance for the precise use of formulae and accurate diagnosis of syndromes. The patient’s response and treatment could be closely monitored with direct or surrogate biomarkers. Formulae efficacy is important for the discovery of effective material basis in TCM. Researchers have therefore made an effort to innovate TCM research methods aimed at solving the effective material basis of TCM formulae.
4. THE CHALLENGES OF TCM In the 21st century, TCM is facing the challenges of internationalization of economic globalization. The biggest obstacle for TCM is that most countries of the world are excluded from formal medicine, and there is no statutory status to protect the existence of alternative medicine. TCM in the European market at present is mostly in the form of food and health products; this not only reduces the status of TCM in the international arena, but also impacts the international share of the herbal medicine market. Meanwhile, since joining the World Trade Organization, with the overall economic development of the pharmaceutical market, the domestic market for TCM has also encountered the impact of “foreign medicine.” How TCM can stably occupy the domestic market will become a major problem in modern medicine. Low exports and weak competitiveness in the market is mainly caused by unstable efficacy, unclear pharmacodynamic material basis, lack of international quality standards, unclear toxicity, etc., but the key factor is that the effective material basis is unclear. Once the material basis is clear, we can clarify the efficacy, develop the internationally recognized quality standards to improve the process and content of active substances, reduce the unwanted or toxic substances, etc. Therefore the characterization of effective material basis has become a “bottleneck,” which restricts the development of TCM. Since TCM knowledge and techniques are mostly clinical expertise inherited and developed from ancient TCM physicians and books, many of which do not have standardized and scientific procedures and criteria, TCM is impeded from disseminating globally. It is necessary to introduce new strategies and technologies into TCM for its standardization and globalization.
5. FUTURE PERSPECTIVE With economic development and rising living standards, people’s concepts of health and way of life have undergone great changes. Disease prevention through TCM, which has a wealth of clinical experience, will become more important in life sciences. The key issue for TCM is how to use the modern technology to discover the effective material basis. The current tide may be turning back to nature in the search for new drug candidates. Millennia-old Chinese medicine treats disease with many combination therapies involving ingredients used in clinic practice. Increasing
5
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CHAPTER 1 Traditional Chinese Medicine
evidence has demonstrated that the clinical use of combinatorial intervention in TCM achieves synergistic interactions that are capable of producing a sufficient effect at low doses. Of note, it beneficially accounts for the popular view that TCM usually takes multicomponents to exert their action. It is hoped that these studies will lay the appropriate foundation for dissecting the novel synergism of multicomponents from TCM to improve therapeutic effects and offer bright prospects for the control of complex diseases in a synergistic manner. It may provide a promising strategy in natural products and new combination medicine patterns derived from TCM.
REFERENCES Fox, J.L., 2015. Obama catapults patient-empowered precision medicine. Nat. Biotechnol. 33 (4), 325. Liu, X., Wu, W.Y., Jiang, B.H., Yang, M., Guo, D.A., 2013. Pharmacological tools for the development of traditional Chinese medicine. Trends Pharmacol. Sci. 34 (11), 620–628. Liu, J., Mu, J., Zheng, C., Chen, X., Guo, Z., Huang, C., Fu, Y., Tian, G., Shang, H., Wang, Y., 2016. Systems-pharmacology dissection of traditional Chinese medicine compound saffron formula reveals multi-scale treatment strategy for cardiovascular diseases. Sci. Rep. 6, 19809. Song, H.P., Wu, S.Q., Hao, H., Chen, J., Lu, J., Xu, X., Li, P., Yang, H., 2016. A chemical family-based strategy for uncovering hidden bioactive molecules and multicomponent interactions in herbal medicines. Sci. Rep. 6, 23840. Tu, Y., 2011. The discovery of artemisinin (qinghaosu) and gifts from Chinese medicine. Nat. Med. 17 (10), 1217–1220. Wang, X., Zhang, A., Wang, P., Sun, H., Wu, G., Sun, W., Lv, H., Jiao, G., Xu, H., Yuan, Y., Liu, L., Zou, D., Wu, Z., Han, Y., Yan, G., Dong, W., Wu, F., Dong, T., Yu, Y., Zhang, S., Wu, X., Tong, X., Meng, X., 2013. Metabolomics coupled with proteomics advancing drug discovery toward more agile development of targeted combination therapies. Mol. Cell Proteom. 12 (5), 1226–1238. Wang, X., Zhang, A., Zhou, X., Liu, Q., Nan, Y., Guan, Y., Kong, L., Han, Y., Sun, H., Yan, G., 2016. An integrated chinmedomics strategy for discovery of effective constituents from traditional herbal medicine. Sci. Rep. 6, 18997. Zhang, A., Sun, H., Wang, X., 2013. Recent advances in natural products from plants for treatment of liver diseases. Eur. J. Med. Chem. 63, 570–577. Zhang, A., Sun, H., Wang, X., 2014. Potentiating therapeutic effects by enhancing synergism based on active constituents from traditional medicine. Phytother. Res. 28 (4), 526–533.
Traditional Chinese Medicine: Current State, Challenges, and Applications
1
Xijun Wang, Aihua Zhang, Hui Sun, Guangli Yan, Ping Wang, Ying Han
1. CURRENT STATE The 2015 Nobel Prize for Physiology or Medicine, won by pharmacologist Youyou Tu, was the first science Nobel Prize awarded to a China-based scientist. Tu’s discovery of artemisinin—a key antimalarial drug credited with saving millions of lives—was rooted in ancient Chinese herbal medicine (Tu, 2011). It has brought traditional Chinese medicine (TCM) to the forefront of the global research community’s attention. Globally, scientists are frequently looking for therapeutic agents from TCM, which is a rich source of potential leads for drug development. Shifting the current drug discovery tide from “finding new drugs” to “screening natural products” may be helpful for overcoming the “more investment, fewer drugs” challenge. The World Health Organization estimates that 80% of the world’s population relies on herbs for their primary health care needs (Zhang et al., 2013). TCM, which is an essential part of the health care system in most Asian countries, relies on natural products and has been playing a very important role in health protection and disease control for thousands of years. TCM therapeutic efficacy, usually attributed to the synergistic property of multiple herbs and constituents, has advocated combinatorial therapeutic strategies called formulae that improve efficacy through hitting multiple targets. Based on syndromes and patient characteristics, and guided by the TCM theory, formulae are designed to contain a combination of various kinds of crude drugs that, when combined, generally assume that a synergism of all ingredients will bring about the maximum of therapeutic efficacy (Fig. 1.1A). Typically, according to the principle of TCM, the herbal formulae include four elements: the monarch (Jun), minister (Chen), assistant (Zuo), and servant (Shi). In TCM formulae, monarch aims at the cardinal pathological symptom of a disease. Minister assists monarch to treat other secondary symptoms, if applicable. Assistant and servant mainly coordinate the formulae, facilitate performances of monarch and minister, and decrease their side effects. They work together harmoniously to achieve an ideal therapeutic outcome. However, the direct effect substances in vivo Serum Pharmacochemistry of Traditional Chinese Medicine. http://dx.doi.org/10.1016/B978-0-12-811147-5.00001-7 Copyright © 2017 Elsevier Inc. All rights reserved.
1
2
CHAPTER 1 Traditional Chinese Medicine
FIGURE 1.1 The Characteristics of Traditional Chinese Medicine (TCM) on Ancient Chinese Philosophy. (A) TCM practitioners often prescribe a combination of herbs called formulae that work together harmoniously to achieve an ideal therapeutic outcome. (B) Formulae consisting of multiherbs possess multicomponent and multitarget characteristics.
2. Application of TCM
are poorly understood and thus hamper the modernization of TCM; they must be addressed using modern analytical techniques coupled with innovative methodology. Some researchers have made good attempts in this area using approaches to identify the multicomponents from herb medicines (Song et al., 2016; Wang et al., 2016). These studies can be considered a useful pilot trial in the effort to evaluate traditional formulae on a larger scale. Furthermore, these observations indicate that traditional formulae usually require multiple components to exert their effects, possibly laying the foundation for promising new schemes and patterns of advancing drug development from active constituents of formulae toward better therapeutic effects. TCM, one of the oldest phytomedicine systems of health care, has been used in Asian countries such as China, Japan, and Korea for thousands of years. Based on its long history of clinical use and wide-ranging effects in the treatment of numerous diseases, especially chronic diseases, TCM is increasingly accepted and used by billions of people around the world. For improving health, practitioners advocated combinatorial therapeutic strategies based on overall symptoms and signs of syndrome and often prescribe formulae that work together harmoniously to achieve ideally therapeutic effects. A single herb already contains thousands of compounds; formulae consisting of multiherbs possess multicomponent and multitarget characteristics (Fig. 1.1B). Compared with chemical drugs, TCM has multicomponent, multitarget, and multipathway characteristics and possesses unparalleled advantages when faced with miscellaneous diseases. This means that the efficacy of TCM depends on the combined action of multiple herbs because it usually contains a lot of ingredients and exerts synergistic therapeutic efficacies. However, this can cause many difficulties in the search for effective substances from TCM.
2. APPLICATION OF TCM TCM is based on ancient Chinese philosophy. Its characteristics include yin yang theories, five element concepts, subjective diagnostic methods, holism, treatment of differential syndromes, dynamic functional aspects, etc. TCM treatment with therapeutic strategies in a holistic fashion is based on overall symptoms and signs of differential syndromes and, from a nonlinear point of view, concerns disease from various dynamic functional aspects. It focuses on the patient rather than the disease, promoting enhanced quality of life. TCM often uses formulae that comprise several types of crude herbs tailored to an individual’s condition based on subjective diagnosis methods. TCM advocates combinatory therapeutic strategies by formulae, in which one represents the key component and others serve as adjuvants to assist the effects or facilitate the delivery of the key components (Wang et al., 2013). According to TCM theory, formulae include four elements: the monarch (which plays the most important role in the formulae), the minister (which increases the effectiveness of the monarch herb), the assistant (which helps the monarch and minister herbs reach their target positions), and the servant (which can reduce the adverse effects and/or increase the potency of the whole formulae).
3
4
CHAPTER 1 Traditional Chinese Medicine
Because of a long cultural heritage and rich natural resources, a wealth of knowledge of traditional medicine has been accumulated in China. At least 11,146 plant species, 1581 animal species, and 80 minerals and substances, ranging from precious stones to mineralized fossils, are used as TCM medicines (Liu et al., 2013). Typically, formulae, which consist of several herbs, would comprise hundreds of compounds as a complex system that contains lots of components with diversities in chemical structures, biological activities, and interactions among compounds, and the content for each component varies greatly. Many Chinese therapeutic herbs traditionally used in the cotreatment but not monotreatment series demonstrate significantly better pharmacological effects, because the combination application of TCM can achieve a synergistic interaction capable of yielding a sufficient effect at low doses. Tremendous progress has been made in the past few years; however, cancer, diabetes, and other complex diseases may limit the performance of the single-target-drug paradigm. Meanwhile, some researchers found that a combination of multiple compounds rather than using a single compound could achieve increased effectiveness (Zhang et al., 2014). With the wave of “returning to nature,” people from all over the world are becoming increasingly interested in the magical effects of the formulae. Like almost all other traditional medicines, at present formulae are still being practiced in their original form and although effective in treating many conditions, they lack necessary scientific research. The lack of a comprehensive understanding of the relationship between syndrome and formulae makes it difficult to advance TCM from modern sciences, which stagnates the development of TCM. For TCM to be modernized, it is critical to use modern tools to determine its mechanism of action.
3. THE COMING ERA OF PRECISION MEDICINE: WHAT CAN WE LEARN FROM CHINESE MEDICINE? President Obama in the State of the Union Address announced the launch of a new Precision Medicine Initiative (Fox, 2015). Precision medicine promises to match the right patient with the right diagnosis, the right treatment, in the right amount. The era of personalized precision medicine is about to emerge. The “personalized treatment” of TCM is consistent with the ideology of precision medicine. Obviously, compared with modern medicine, TCM leans toward “precision,” reflecting “personalized medicine,” because it has a complete theoretical system and a mature method for the diagnosis of an individual’s condition. After the development and improvement of TCM by ancient physicians, TCM formed the coordination of theory and practice of precise diagnosis and precise treatment in a dynamic state. Chinese medicine adjusts the physique of patients by way of syndrome differentiation, something that Western medicine cannot do. TCM treatment in a holistic fashion is based on overall symptoms and signs of syndromes, and concerns disease from various dynamic functional aspects (Liu et al., 2016). It focuses on the patient rather than the disease, promoting and enhancing the quality of life. TCM often uses formulae that are comprised of several crude herbs tailored to an individual’s condition based on
5. Future Perspective
subjective diagnosis. Interestingly, to improve clinical efficacy, formulae variation with syndrome and formulae corresponding syndrome have practical significance for the precise use of formulae and accurate diagnosis of syndromes. The patient’s response and treatment could be closely monitored with direct or surrogate biomarkers. Formulae efficacy is important for the discovery of effective material basis in TCM. Researchers have therefore made an effort to innovate TCM research methods aimed at solving the effective material basis of TCM formulae.
4. THE CHALLENGES OF TCM In the 21st century, TCM is facing the challenges of internationalization of economic globalization. The biggest obstacle for TCM is that most countries of the world are excluded from formal medicine, and there is no statutory status to protect the existence of alternative medicine. TCM in the European market at present is mostly in the form of food and health products; this not only reduces the status of TCM in the international arena, but also impacts the international share of the herbal medicine market. Meanwhile, since joining the World Trade Organization, with the overall economic development of the pharmaceutical market, the domestic market for TCM has also encountered the impact of “foreign medicine.” How TCM can stably occupy the domestic market will become a major problem in modern medicine. Low exports and weak competitiveness in the market is mainly caused by unstable efficacy, unclear pharmacodynamic material basis, lack of international quality standards, unclear toxicity, etc., but the key factor is that the effective material basis is unclear. Once the material basis is clear, we can clarify the efficacy, develop the internationally recognized quality standards to improve the process and content of active substances, reduce the unwanted or toxic substances, etc. Therefore the characterization of effective material basis has become a “bottleneck,” which restricts the development of TCM. Since TCM knowledge and techniques are mostly clinical expertise inherited and developed from ancient TCM physicians and books, many of which do not have standardized and scientific procedures and criteria, TCM is impeded from disseminating globally. It is necessary to introduce new strategies and technologies into TCM for its standardization and globalization.
5. FUTURE PERSPECTIVE With economic development and rising living standards, people’s concepts of health and way of life have undergone great changes. Disease prevention through TCM, which has a wealth of clinical experience, will become more important in life sciences. The key issue for TCM is how to use the modern technology to discover the effective material basis. The current tide may be turning back to nature in the search for new drug candidates. Millennia-old Chinese medicine treats disease with many combination therapies involving ingredients used in clinic practice. Increasing
5
6
CHAPTER 1 Traditional Chinese Medicine
evidence has demonstrated that the clinical use of combinatorial intervention in TCM achieves synergistic interactions that are capable of producing a sufficient effect at low doses. Of note, it beneficially accounts for the popular view that TCM usually takes multicomponents to exert their action. It is hoped that these studies will lay the appropriate foundation for dissecting the novel synergism of multicomponents from TCM to improve therapeutic effects and offer bright prospects for the control of complex diseases in a synergistic manner. It may provide a promising strategy in natural products and new combination medicine patterns derived from TCM.
REFERENCES Fox, J.L., 2015. Obama catapults patient-empowered precision medicine. Nat. Biotechnol. 33 (4), 325. Liu, X., Wu, W.Y., Jiang, B.H., Yang, M., Guo, D.A., 2013. Pharmacological tools for the development of traditional Chinese medicine. Trends Pharmacol. Sci. 34 (11), 620–628. Liu, J., Mu, J., Zheng, C., Chen, X., Guo, Z., Huang, C., Fu, Y., Tian, G., Shang, H., Wang, Y., 2016. Systems-pharmacology dissection of traditional Chinese medicine compound saffron formula reveals multi-scale treatment strategy for cardiovascular diseases. Sci. Rep. 6, 19809. Song, H.P., Wu, S.Q., Hao, H., Chen, J., Lu, J., Xu, X., Li, P., Yang, H., 2016. A chemical family-based strategy for uncovering hidden bioactive molecules and multicomponent interactions in herbal medicines. Sci. Rep. 6, 23840. Tu, Y., 2011. The discovery of artemisinin (qinghaosu) and gifts from Chinese medicine. Nat. Med. 17 (10), 1217–1220. Wang, X., Zhang, A., Wang, P., Sun, H., Wu, G., Sun, W., Lv, H., Jiao, G., Xu, H., Yuan, Y., Liu, L., Zou, D., Wu, Z., Han, Y., Yan, G., Dong, W., Wu, F., Dong, T., Yu, Y., Zhang, S., Wu, X., Tong, X., Meng, X., 2013. Metabolomics coupled with proteomics advancing drug discovery toward more agile development of targeted combination therapies. Mol. Cell Proteom. 12 (5), 1226–1238. Wang, X., Zhang, A., Zhou, X., Liu, Q., Nan, Y., Guan, Y., Kong, L., Han, Y., Sun, H., Yan, G., 2016. An integrated chinmedomics strategy for discovery of effective constituents from traditional herbal medicine. Sci. Rep. 6, 18997. Zhang, A., Sun, H., Wang, X., 2013. Recent advances in natural products from plants for treatment of liver diseases. Eur. J. Med. Chem. 63, 570–577. Zhang, A., Sun, H., Wang, X., 2014. Potentiating therapeutic effects by enhancing synergism based on active constituents from traditional medicine. Phytother. Res. 28 (4), 526–533.